tbuckley/cabot-search huggingface dataset:
EXTH-85. EPHA3 CART: DUAL TARGETING OF GLIOBLASTOMA AND TUMOR MICROENVIRONMENT
Authors: Michael Ruff, Ekene Ogbodo, Elizabeth Siegler, Leo Sakemura, Jann Sarkaria, Saad Kenderian
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In GBM, effective chimeric antigen receptor T-cell (CART) therapy remains a challenge; immunosuppressive components within the tumor microenvironment (TME) inhibit CART cells. EphA3 is a receptor tyrosine kinase with low expression in adult tissues but is highly expressed in tumor neovasculature and tumor stromal cells in GBM and other solid tumors. METHODS We performed RNA sequencing and Immunohistochemical staining for of EphA3 in a clinically annotated GBM PDX biobank and M01 M1 and M2 polarized macrophages. We then investigated the suppressive capability of M2 macrophage on EphA3-CART in an SNB-19 GBM cell co-culture. We tested the antiantitumor potential of EphA3-CART against luciferase+ SNB-19 GBM cells in vivo with flank and orthotopically engrafted NOD-SCID-ɣ-/- (NSG) mice. Engraftment was confirmed by bioluminescent imaging (BLI) and vernier caliber (flank) for 7-14 days post-injection. Mice were randomized to be treated with EphA3-CART or untransduced T-cells (UTD). Subsequently tumor size and mouse survival was monitored to determine the antitumor effect. RESULTS EphA3 was highly expressed on GBM PDX models as well as M2 macrophages. Compared to M0 and M1 macrophages, M2 macrophages significantly suppressed EphA3-CART However, despite the suppressive activity of the M2 macrophage, EphA3-CART exhibited significant antitumor activity . In both flank and orthotopically implanted mouse models, there was an observed reduction in tumor volume with EphA3-CART treated model compared to the UTD counterpart. EphA3-CART treatment resulted in significantly improved survival of the treated models compared to UTD models (hazard ratio = 0.053 **p = 0.005). CONCLUSION We demonstrate that EphA3 is expressed on GBM cells as well as on M2 macrophages. EphA3 CART is able to overcome and ameliorate the effect of a major component of the tumor microenvironment (TME), M2 macrophages. EphA3 CART appears effective in flank and orthotopic mouse models of GBM.
QLTI-05. COST TOXICITY OF ORAL CHEMOTHERAPY IN PRIMARY BRAIN TUMOR PATIENTS
Authors: Mallika Patel, Mary L Affronti, Evan Buckley, James Herndon, Eric Lipp, Emma Mackowsky, Margaret O Johnson, Henry Friedman, David Ashley, Jung-Young Kim, Katherine Peters
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Costs associated with cancer treatments in the United States continue to rise as new therapies are approved. Financial toxicity describes both the quantifiable costs associated with cancer as well as the distressful effects related to the costs of treatment. METHODS The goal of this study is to better understand the financial burden of oral chemotherapies on patients with primary brain tumors from their perspective. Following one cycle of oral chemotherapy, we contacted patients per IRB-approved protocol to participate in a 20-question survey (COST-FACIT and other questions relevant to insurance and cost). With descriptive statistics, we summarized survey responses overall and within strata defined by on-label or off-label oral medication use. RESULTS Sixty surveys were completed (58 total patients; 2 completed surveys for a second treatment). Most surveys (n = 53, 88%) reflected on-label therapy use, with only 7 patients (12%) on off-label therapies. The mean overall financial toxicity score was 23.1 (range: 1 – 44); the lower the financial toxicity score, the greater the financial distress of study participants. When asked if their provider discussed treatment cost before initiation, 21 patients (35%) stated that they did, and 39 patients (65%) said they did not discuss cost or did not recall a discussion. However, in the off-label therapies cohort, all 7 patients stated that their provider discussed cost before prescribing. Majority of surveys (70%) noted patient copays associated with these medications. Nine patients (17%) in the on-label group and three patients (43%) in the off-label group had chemotherapy-associated costs that caused negative effects on quality of life. CONCLUSIONS Although the groups are disproportionate, a higher percentage of financial distress occurred in the off-label therapy group. While cost discussions are challenging, they remain an important part of therapy initiation that may decrease undue stress; this will be an area of improvement.
DDEL-09. SATURATED FATTY ACID EMULSION OPENS THE BLOOD-BRAIN BARRIERS AND ENHANCES DRUG DELIVERY
Authors: Kyoung Su Sung, Won-Ho Cho, Hak Jin Kim
Journal: Neuro-Oncology (2023)

Abstract PURPOSE To evaluate whether saturated fatty acid (SFA) emulsion affects the BBB and whether drug delivery is promoted with the aid of SFA in the brain. MATERIAL AND METHODS Each SFA (butyric, valeric, caproic, enantic and caprylic acid) emulsion was infused into the right common carotid artery in a rat model. Trypan blue staining for qualitative and semiquantitative analysis of the BBB opening was performed. A transmission electron microscopic (TEM) exam with the contrast media for morphologic evaluation of the tight junction was obtained. Delivery of doxorubicin in the brain was determined by fluorometric analysis. Delivery of temozolomide (TMZ) through the BBB was studied by desorption electrospray ionization (DESI)-MS imaging. RESULTS The ipsilateral hemisphere revealed positive trypan blue staining in all five SFA emulsion groups. Ratios of the ipsilateral to the contralateral hemisphere of in trypan blue permeability with hue analysis was above 1.0. As the carbon number in the used SFA increased, the ratio of trypan blue permeability increased and was statistically significant (P &amp;lt; 0.05). The tight junction and neural interstitium were filled with the contrast media in all five SFA emulsion groups. Delivery of doxorubicin (P &amp;lt; 0.05) and TMZ were significantly high in the ipsilateral hemisphere compared to the contralateral hemisphere. In the caprylic acid group, the BBB opening and drug delivery were highest among the five SFA groups. CONCLUSION SFA emulsion with intraarterial infusion opened the BBB and drug delivery was enhanced consequently. Thus, SFA emulsion might be another strategy for the research of BBB opening and promotion of drug delivery in the brain.
CTNI-18. DESIGNING AND DELIVERING A RANDOMISED CONTROLLED TRIAL OF MEDICINAL CANNABINOIDS IN RECURRENT GLIOBLASTOMA - THE ARISTOCRAT TRIAL
Authors: Susan Short, Joshua Savage, Rhys Mant, Amit Patel, Peter Buckle, Sarah Meade, Florien Boele, Emma Banks, Lucy Brazil, Fiona Collinson, Lucinda Billingham
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND ARISTOCRAT is a randomised, double-blind, placebo-controlled phase II trial of temozolomide chemotherapy, with or without cannabinoids (Nabixomols) in patients with MGMT-methylated recurrent GBM and has recently opened to recruitment across the UK. METHODS A multi-disciplinary team of co-applicants and trial management group (TMG) members was assembled comprising clinicians, statisticians, trialists, Patient &amp; Public Involvement (PPI), pharmacists and quality of life (QoL) researchers to design a pragmatic phase II randomised study. The protocol randomises on a 2:1 ratio between Nabiximols or matched placebo alongside standard dose temozolomide in patients at first recurrence of IDH wild-type GBM. Patients titrate to an individualised dose based on tolerance to a maximum of 12 oro-mucosal sprays per day. The primary outcome measure is overall survival time with key secondary outcomes including survival at 6, 12 and 24 months, progression-free survival time, health-related QoL and adverse events. Intermediate assessment of feasibility to confirm safety, compliance and achievability of recruitment will be undertaken after 40 patients are randomised. PPI input has been critical in ensuring sensitive and appropriate patient &amp; public messaging and in developing patient information videos. RESULTS ARISTOCRAT was rapidly funded via a novel crowdfunding campaign organised by The Brain Tumour Charity during the COVID-19 pandemic. The trial office has since responded to &amp;gt;150 patient enquiries, demonstrating the high level of patient and public enthusiasm for this trial. Coverage in the press also shows a more broad level of interest in the use of cannabis-derived medicines. The study opened to recruitment on 03-Feb-2023 and the first patient was recruited on 08-Mar-2023. The study aims to recruit a total of 234 patients over an 18 month period. CONCLUSION ARISTOCRAT will provide robust clinical data on the role of cannabinoids in improving overall survival and the impact on QoL for patients with recurrent GBM.
EXTH-69. REGULATION OF N1/N2 NEUTROPHIL PHENOTYPE BY A MANZAMINE-DERIVED COMPOUND FOR BRAIN TUMOR TREATMENT
Authors: Ya-Jui Lin, Chiungyin Huang, Kuo-Chen Wei, Pin-Yuan Chen
Journal: Neuro-Oncology (2023)

Abstract In cancer microenvironment, the presence of neutrophils is associated with tumor proliferation, invasion and immunomodulation. The tumor associated neutrophils (TAN) can be polarized toward N1 (anti-tumor) or N2 (pro-tumor) phenotypes. Therefore, modulating neutrophil phenotype may serve as brain tumor treatment strategy. We use immunosuppressive and normal mice bearing brain tumor cell xenograft to study the role of TANs in tumor progression. A manzamine-derived compound 1-(9’-propyl-3’-carbazole)-1, 2, 3, 4-tetrahydro-β-carboline (PCTC) was used to treat brain tumor mice. In brain tumor tissue, flowcytometry study revealed the amount of pro-tumor N2 TAN is significantly greater than anti-tumor N1 subtype. While PCTC was intracranial administrated into brain tumor, the ratio of N1/N2 is reversed. Immunochemical staining showed increasing neutrophils in tumor at day 1 post treatment, followed by subsequent T cell and macrophage gathering at day 5. Cytokine array results revealed the expression level of CXCL9/CXCL10 were upregulated in PCTC treatment glioma cells and brain tumor tissues. Cell study also demonstrated T cell migration ability was significantly increased when co-cultured with neutrophil and PCTC treated glioma cells. In mice tumor model, NU/NU mouse lack of T cell represented no response to PCTC treatment, while significant tumor shrunken was observed in B6 mice. Compensation study by intravenous inoculation of T cell and PCTC to NU/NU glioma mice showed flavor response to animal survival. In this study, we demonstrated the N1/N2 ratio of TAN can be regulated by PCTC, and be beneficial to glioma treatment. Furthermore, PCTC acts on tumor cells, together with TAN to attract T cell by increase CXCL9/CXCL10. Anti-tumor N1 and subsequent T cell gathering both contribute to tumor cell killing. As a conclusion, neutrophil phenotype can be modulated, and cooperated with T cells to serve as a new glioma treatment strategy.
PATH-13. APPLICATIONS OF SPATIAL TRANSCRIPTOMICS FOR THE DIAGNOSTICS OF GLIOMAS
Authors: Michael Ritter, Christina Blume, Yiheng Tang, Bhuvic Patel, Areeba Patel, Philipp Sievers, Zaira Seferbekova, Natalie Berghaus, Christel Herold-Mende, Wolfgang Wick, Moritz Gerstung, Andreas von Deimling, Dieter Henrik Heiland, Felix Sahm
Journal: Neuro-Oncology (2023)

Abstract Due to their infiltrative growth, diffuse gliomas can pose a major challenge for neuropathologists. Lack of specific immunohistochemistry markers for some gliomas like IDH-wildtype glioblastoma can make it hard to identify the tumour cell content or distinguish between tumour and reactive gliosis. Other hurdles are high fractions of DNA from healthy cells in molecular diagnostic analysis, or scarce tissue, which can result in a failed DNA extraction. To overcome these limitations, we evaluated the application of spatial transcriptomics on 14 glioblastoma bulk resections and 18 stereotactic biopsies of 7 glioblastoma, IDH wildtype, 4 oligodendroglioma IDH-mutant and 7 astrocytoma IDH-mutant samples with the aim to generate a diagnostic report containing all information needed by the neuropathologist and clinician. Using the SPATA2 R package, we were able to infer the copy number variation (CNV) profiles for each spot. When comparing the inferred CNVs to the CNVs calculated by the 850K methylome analysis, a correlation between CNVs identified from the 850K data and the inferred CNVs could be seen. For diagnostic relevant CNVs of chr. 7, 10, 1p and 19q, the inferred CNVs were concordant with the 850K data in 100% of the cases with confirmed tumour tissue. CNVs from spatial transcriptomics were able to reveal sub-clones, which could not be detected by the 850K array data. The CNVs could then be used in combination with a deconvolution approach to determine the tumour burden of the tissue. Using RNA expression, the immunohistochemistry staining of important diagnostic markers like NeuN, GFAP and Ki67 was predicted. In addition, the spatial gene expression could be used to identify the glioblastoma subtype based on the gene expression of different methylation subtypes. All the above-mentioned analysis also generated meaningful results for tissue fragments smaller than 1mm in diameter, which are too small for molecular diagnostic analysis.
EPCO-25. HETEROGENEITY OF INSERTION/DELETION AND SINGLE NUCLEOTIDE VARIATION IN DRIVERS OF LOWER GRADE GLIOMAS
Authors: Lee Chen, Nicholas Stevers, Joseph Costello
Journal: Neuro-Oncology (2023)

Abstract Single nucleotide variation (SNV) and copy number variation (CNV) have been extensively studied across tumor types. Their impact on tumor evolution has been a primary research focus. However, insertion/deletion (indels) have received less attention due to their high false positive and false negative rate and the absence of hotspot indel sites. We examine adult IDH wildtype/mutant gliomas, and utilize spatially mapped samples within the same tumors (84 tumors, averaging 8 to 9 samples/tumor), as well as primary/recurrent paired samples (n=37), to investigate the heterogeneity and progression of indels and SNVs. We used two indel-detecting algorithms, Pindel and Muect2, and discovered and validated several indels, which had not been previously emphasized, including in TCHH. We report on two frequently mutated driver genes, CIC and ATRX, in IDHmut-Codel and IDHmut-noncodel gliomas, respectively. CIC SNVs and indels are observed as complementary occurrences. For example, among 9 samples of the tumor recurrence of one patient, 6 showed CIC SNVs, with only two sharing the same mutation. In contrast, 8 of 9 samples exhibited CIC indels, representing 4 different types. Notably, all samples displayed either CIC SNVs or indels. In IDHmut-noncodel tumors, a similar pattern was observed with ATRX. Nonetheless, all samples displayed either ATRX SNVs or indels. This study highlights the tremendous intratumor heterogeneity and evolution in drivers of LGG, emphasizing their complex role in tumorigenesis. Prior studies may have underestimated the frequency and heterogeneity due to calling accuracy and limitations in tumor sampling. By focusing on indels and other genetic variations within gliomas, this study sheds light on their significance in understanding tumor progression, the essential nature of CIC and ATRX inactivation over whole tumors, and the potential implications for therapeutic interventions.
EXTH-59. IDENTIFICATION OF GROWTH HORMONE RECEPTOR AS A RELEVANT TARGET FOR PRECISION MEDICINE IN LOW-EGFR EXPRESSING GLIOBLASTOMA
Authors: Maite Verreault, Irma Segoviano Vilchis, Shai Rosenberg, Nolwenn Lemaire, Charlotte Schmitt, Jeremy Guehennec, Louis Royer-Perron, Jean-Leon Thomas, Tukiet T Lam, Florent Dingli, Damarys Loew, Francois Ducray, Sophie Paris, Catherine Carpentier, Yannick Marie, Florence Laigle-Donadey, Audrey Rousseau, Natascha Pigat, Florence Boutillon, Franck Bielle, Karima Mokhtari, Stuart J Frank, Aurelien de Reynies, Khe Hoang-Xuan, Marc Sanson, Vincent Goffin, Ahmed Idbaih
Journal: Neuro-Oncology (2023)

Abstract New therapeutic approaches are needed to improve the prognosis of Glioblastoma (GBM) patients. With the objective of identifying alternative oncogenic mechanisms to abnormally activated EGFR signaling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samples. We identified that Growth Hormone Receptor (GHR) signaling defines a distinct molecular subset of GBMs devoid of EGFR overexpression. GHR overexpression was detected in one third of patients and was associated with low levels of SOCS2 expression due to SOCS2 promoter hypermethylation. In GBM patient-derived cell lines, GHR signaling modulates the expression of proteins involved in cellular movement, promotes cell migration, invasion and proliferation in vitro, and promotes tumorigenesis, tumor growth and tumor invasion in vivo. GHR genetic and pharmacological inhibition reduced cell proliferation and migration in vitro. GHR signaling pathway thus emerges as an oncogenic signaling pathway in low EGFR-expressing GBMs and as a promising therapeutic target. This study pioneers a new field of investigation to improve the prognosis of GBM patients.
MODL-33. PATIENT-DERIVED GLIOBLASTOMA MINIATURE AND CANCER STEM CELL SUICIDE-INDUCING NANO-AWAKENER BASED ON IT
Authors: Seon-Jin Yoon, Sewoom Baek, Seung-Eun Yu, Euna Jo, Ran Joo Choi, Ju Hyung Moon, Eui-Hyun Kim, Jong Hee Chang, Hak-Joon Sung, Seok-Gu Kang
Journal: Neuro-Oncology (2023)

Abstract Patient-specific anti-tumor therapies can evolve by vitalizing the mother tissue-like cancer niche, cellular profile, genetic signature, and drug responsiveness. This evolution elucidated a key mechanism along with the development of the cancer therapy. The present study aimed to meet these clinical demands by approaching the direct culture of GBM patient tissues with a 1 mm post-punching diameter in a 3D microchannel network chip (“GBM miniature”). Hence, we directly cultured of GBM patient tissue (1 mm diameter) in a microchannel network chip (GBM miniature) to preserve mother tissue-like characteristic signatures and microenvironment. When chemoradiation therapy were administered within 1 day, the responsiveness of the tissue in the chip mirroring the clinical outcomes. The characteristics of migrating cells from GBM miniature were analyzed, and peptides that target these migrating CSCs were searched for. And, by attaching this CSC peptide to the nanovesicle, the therapeutic effect was confirmed in GBM miniature. Upon testing within 1 day, the tissue chip reflected patient drug responsiveness as seen in the clinic. As the tissue chip culture was continued, the intact GBM signature was getting lost, and the outward migration of stem cells from the tissue origin increased, indicating a leaving-home effect on the family dismantle. Nanovesicle production using GBM stem cells enabled self-chasing of the cells that escaped the temozolomide effect owing to quiescence. The anti-PTPRZ1 peptide display and temozolomide loading to nanovesicles awaked stem cells from the quiescent stage to death. This research proposes a GBM patient avatar platform and mechanism-learned nanotherapy for translation.
EXTH-75. A MACROPHAGE-BASED DRUG DELIVERY PLATFORM FOR GLIOMA TREATMENT
Authors: Miaomiao Sun, Maciej Bialasek, Tomasz Rygiel, Michael Weller, Magdalena Krol, Tobias Weiss
Journal: Neuro-Oncology (2023)

Abstract There is an urgent need for more effective treatment strategies against gliomas. Even though various drugs have potent anti-tumor activity in vitro, their application in vivo is limited by ineffective delivery and systemic toxicity. Therefore, novel strategies are needed to deliver these drugs effectively and safely to the tumor site. Here, we developed an adoptive transfer strategy against malignant brain tumors utilizing monocyte-derived macrophages that are loaded with ferritin-protein cages containing drugs or other proteins and transfer these nanocarriers effectively to cancer cells for intracellular release and cancer cell killing. Using flow cytometry and microscopy, we observed a high transfer efficiency of ferritin-cages from loaded macrophages into human and mouse glioma cells in vitro in co-culture assays. We also confirmed the transfer of ferritin-cages from macrophages to glioma cells in vivo upon intravenous or intratumoral treatment of GL-261 or CT-2A glioma-bearing mice using in vivo imaging and ex vivo flow cytometry and microscopy. To study the anti-glioma activity with therapeutically active payloads, we loaded murine/human macrophages with ferritin cages carrying cytotoxic auristatin. Co-culture of these loaded macrophages with murine or human glioma cells in vitro revealed a time- and concentration-dependent cytotoxicity to glioma cells. In vivo, intravenous or intratumoral administration of ferritin-drug protein cages was tolerated without toxicities and conferred a survival benefit in two orthotopic murine glioma models (GL-261 and CT-2A) leading to a large fraction of long-term surviving mice. Interactome studies of ferritin-cage-binding proteins revealed phagocytic and cytoskeleton re-arrangement pathways to be involved in uptake and transfer of ferritin-cages from macrophages to glioma cells. This ‘Trojan Horse’ approach based on macrophages-ferritin-protein cages constitutes a promising platform to deliver cytotoxic drugs effectively and safely to gliomas and provides a rationale for clinical translation.
SURG-06. DEVELOPING A LASER INTERSTITIAL THERMAL THERAPY (LITT) PLATFORM FOR THE TREATMENT OF INTRACRANIAL LESIONS IN CANINES
Authors: Lucas Wachsmuth, Laura Ruterbories, Vadim Tsvankin, Alexa Bramall, Richard Tyc, Christopher Mariani, Peter Fecci
Journal: Neuro-Oncology (2023)

Abstract Malignant gliomas are devastating intracranial tumors with dismal prognoses that impose unique therapeutic challenges. Treatment options include surgical resection, radiation, and chemotherapy, but efficacy is limited and carries associated morbidity. Promise persists for newer modalities, such as immune-based platforms, but obstacles include limited therapeutic access due to the blood-brain barrier (BBB) and the highly immunosuppressive tumor microenvironment. Laser interstitial thermal therapy (LITT) is a minimally invasive surgical intervention permitting thermal ablation of intracranial tumors. During LITT, a laser probe is stereotactically placed in the lesion through a skull burr hole. Real-time MRI is used to calculate thermal dosage zones to monitor ablation progress. LITT is not only cytoreductive but also opens the BBB and induces a powerful hyperthermia-driven anti-tumor immune response; it thus may synergize with other emerging therapies. Spontaneous canine glioma offers a matchless, optimally recapitulative appropriately sized tumor model, providing a unique opportunity to investigate and optimize the LITT platform. We adapted a commercially available LITT system (Monteris Medical) for application in canines with intracranial lesions. Initially, canine cadavers were used to optimize LITT procedures; we then performed LITT in live dogs. Our approach consists of 1. obtaining volumetric MRI studies for trajectory planning, 2. fixing canine patients to the surgical bed, 3. registering anatomic landmarks (Brainlab) to a volume rendered image, 4. using an integrated instrument holder (Varioguide, Brainlab) to guide drilling of 4.5 mm skull burr holes for placement of self-tapping titanium “mini-bolts” (Monteris Medical), and 5. introducing the laser through the mini-bolts for ablation in the MRI suite. This method allows for rigid stereotaxy, successful neuronavigation, and a minimally invasive approach. We have successfully performed LITT on four canine patients with intracranial gliomas. Future studies will explore immunologic mechanisms underlying the post-LITT anti-tumor response as well as combination therapeutic platforms, including nanoparticles and stereotactic radiotherapy.